Discovery of Selective Estrogen Receptor Covalent Antagonists for the Treatment of ERαWT and ERαMUT Breast Cancer.
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ICR Authors
Authors
Puyang, X
Furman, C
Zheng, GZ
Wu, ZJ
Banka, D
Aithal, K
Agoulnik, S
Bolduc, DM
Buonamici, S
Caleb, B
Das, S
Eckley, S
Fekkes, P
Hao, M-H
Hart, A
Houtman, R
Irwin, S
Joshi, JJ
Karr, C
Kim, A
Kumar, N
Kumar, P
Kuznetsov, G
Lai, WG
Larsen, N
Mackenzie, C
Martin, L-A
Melchers, D
Moriarty, A
Nguyen, T-V
Norris, J
O'Shea, M
Pancholi, S
Prajapati, S
Rajagopalan, S
Reynolds, DJ
Rimkunas, V
Rioux, N
Ribas, R
Siu, A
Sivakumar, S
Subramanian, V
Thomas, M
Vaillancourt, FH
Wang, J
Wardell, S
Wick, MJ
Yao, S
Yu, L
Warmuth, M
Smith, PG
Zhu, P
Korpal, M
Furman, C
Zheng, GZ
Wu, ZJ
Banka, D
Aithal, K
Agoulnik, S
Bolduc, DM
Buonamici, S
Caleb, B
Das, S
Eckley, S
Fekkes, P
Hao, M-H
Hart, A
Houtman, R
Irwin, S
Joshi, JJ
Karr, C
Kim, A
Kumar, N
Kumar, P
Kuznetsov, G
Lai, WG
Larsen, N
Mackenzie, C
Martin, L-A
Melchers, D
Moriarty, A
Nguyen, T-V
Norris, J
O'Shea, M
Pancholi, S
Prajapati, S
Rajagopalan, S
Reynolds, DJ
Rimkunas, V
Rioux, N
Ribas, R
Siu, A
Sivakumar, S
Subramanian, V
Thomas, M
Vaillancourt, FH
Wang, J
Wardell, S
Wick, MJ
Yao, S
Yu, L
Warmuth, M
Smith, PG
Zhu, P
Korpal, M
Document Type
Journal Article
Date
2018-09-01
Date Accepted
2018-06-19
Abstract
Mutations in estrogen receptor alpha (ERα) that confer resistance to existing classes of endocrine therapies are detected in up to 30% of patients who have relapsed during endocrine treatments. Because a significant proportion of therapy-resistant breast cancer metastases continue to be dependent on ERα signaling, there remains a critical need to develop the next generation of ERα antagonists that can overcome aberrant ERα activity. Through our drug-discovery efforts, we identified H3B-5942, which covalently inactivates both wild-type and mutant ERα by targeting Cys530 and enforcing a unique antagonist conformation. H3B-5942 belongs to a class of ERα antagonists referred to as selective estrogen receptor covalent antagonists (SERCA). In vitro comparisons of H3B-5942 with standard-of-care (SoC) and experimental agents confirmed increased antagonist activity across a panel of ERαWT and ERαMUT cell lines. In vivo, H3B-5942 demonstrated significant single-agent antitumor activity in xenograft models representing ERαWT and ERαY537S breast cancer that was superior to fulvestrant. Lastly, H3B-5942 potency can be further improved in combination with CDK4/6 or mTOR inhibitors in both ERαWT and ERαMUT cell lines and/or tumor models. In summary, H3B-5942 belongs to a class of orally available ERα covalent antagonists with an improved profile over SoCs.Significance: Nearly 30% of endocrine therapy-resistant breast cancer metastases harbor constitutively activating mutations in ERα. SERCA H3B-5942 engages C530 of both ERαWT and ERαMUT, promotes a unique antagonist conformation, and demonstrates improved in vitro and in vivo activity over SoC agents. Importantly, single-agent efficacy can be further enhanced by combining with CDK4/6 or mTOR inhibitors. Cancer Discov; 8(9); 1176-93. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 1047.
Citation
Cancer discovery, 2018, 8 (9), pp. 1176 - 1193
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
2159-8274
eISSN
2159-8290
Collections
Research Team
Endocrinology